Cholecystokinin (CCK) is a neuropeptide found in both gastrointestinal tissue and the tissues of the central nervous system. Compounds which are CCK and gastrin antagonists are useful in the treatment and prevention of CCK and gastrin-related disorders of the gastrointestinal, central nervous, and appetite regulatory systems of warm-blooded vertebrates. One class of compounds exhibiting the desired CCK receptor binding properties are compounds of the formula 1. ##STR1## wherein
R.sup.1 and R.sup.2 are independently hydrogen, C.sub.1 -C.sub.6 alkyl, phenyl, benzyl, naphthyl, pyridyl or substituted phenyl having 1, 2, or 3 substituents selected from the group consisting of C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkylthio, chloro, fluoro, trifluoromethyl, phenyl, phenoxy, phenyl(C.sub.1 -C.sub.4 alkyl), phenyl(C.sub.1 -C.sub.4 alkoxy), cyano, carbamyl, methylenedioxy, C.sub.3 -C.sub.6 alkene, amino, --NH(C.sub.1 -C.sub.4 alkyl or benzyl), and N(C.sub.1 -C.sub.4 alkyl ) 2;
R.sup.3 is hydrogen, C.sub.1 -C.sub.6 alkyl, carboxymethyl, C.sub.1 -C.sub.4 alkoxycarbonylmethyl or a group of the formula ##STR2## wherein
t is 1 or 0; A is --CH.sub.2 --, --O--, --NH-- or --N(C.sub.1 -C.sub.6 alkyl)--; and Y is phenyl or substituted phenyl as defined above;
R.sup.4 is hydrogen or a group of the formula ##STR3## wherein
B is O or S; X is selected from the phenyl substituents defined above; m is O, 1 or 2; n is 0 or 1; Q is --NH--, --N(C.sub.1 -C.sub.6 alkyl)--, --S--, or --O--; and R.sup.12 is a group of the formula --[CH(R.sup.10)].sub.q --(CH.sub.2).sub.r --R.sup.11 wherein R.sup.10 is hydrogen or C.sub.1 -C.sub.6 alkyl; q is 0 or 1; r is 0, 1 or 2; and R.sup.11 is hydrogen, C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.8 cycloalkyl, pentafluorophenyl, pyridyl, tetrahydronaphthyl, indolyl, quinolinyl, phenyl, naphthyl, or phenyl or naphthyl substituted with 1, 2, or 3 substituents as defined above for phenyl; or the group --(Q).sub.n R.sup.12 is 2-tetrahydroisoquinolinyl; and the pharmaceutically acceptable salts thereof.
Compounds of Formula 1 are described in published European patent application No. 91306374.9 (publication No. 0467 614 A1). The artisan will recognize that published European patents are readily available to the artisan in the United States. European patent applications are published in English so that the American artisan can easily read the publication.
The (+)-4(S),5(R)-enantiomer of certain trans isomers of compounds of formula 1 (i.e. (+)-1a infra.) have proven to be potent and selective antagonists of the CCK-B receptor subtype. ##STR4## The antipodal (-)-4(R),5(S)-enantiomers of Formula 1 (i.e. (-)-1a infra. ) are potent and selective antagonists of the CCK-A receptor. ##STR5## Small quantities of these materials have been isolated in enantiomerically pure form by high performance liquid chromatograpic resolution of diastereomeric derivatives of a racemic pyrazolidinone precursor. However, such methods have proven to be intractable for the generation of more than milligram quantities of pure enantiomers.
No general strategies have been reported or suggested in the literature for the enantioselective synthesis of compounds of formula 1. Known strategies for the synthesis of racemic variants of such compounds do not provide for the control of absolute stereochemistry at C-4 and C-5. This invention provides a process for the enantioselective synthesis of either (+)-1a or (-)-1a in a high degree of enantiomeric purity. Futhermore this invention provides new chemical compositions which are useful and necessary for the process claimed herein.